Cardiometabolic profiles in children and adults with overweight and obesity and down syndrome.

Individuals with Down syndrome (DS) are at increased risk for being overweight/obese, but the associated cardiometabolic risk (CR) is not clear. Cross-sectional anthropometric and clinical laboratory data from a multi-site, international cohort of individuals with DS were analyzed to determine cardiometabolic risk by reporting observed distributions of cardiometabolic biomarkers in overweight/obese individuals with DS throughout the lifespan. Descriptive statistics and regression analyses by age categories determined the distributive percentiles for cardiometabolic biomarkers and tested for adiposity as a predictor of CR. Across seven DS clinics, data were collected on 240 patients between the ages of 3 and 63 years, with one quarter overweight and three quarters obese among children and nearly all adults being obese. In children and adults, most cardiometabolic biomarker profiles showed distributive values within normal ranges. Blood lipids were positively associated with body mass index (BMI) in children (high density lipid-cholesterol, p = 0.01; low density lipid-cholesterol, p = 0.02). Levels of hs-CRP were elevated in both children and adults, with BMI positively associated with hs-CRP in adults with DS (p = 0.04). Liver enzyme values were positively associated with BMI in children and adults. The data suggest that in contrast to the general population, in individuals with Down syndrome, being overweight and obese does not appear to confer a significantly increased risk for cardiometabolic disease by biomarker profile. Individuals with DS who are overweight/obese appear to have unique cardiometabolic profiles unrelated to adiposity, notable for increased hs-CRP and normal HA1c levels.

Vernal keratoconjunctivitis in Down syndrome: a case report.

BACKGROUND: Down syndrome (DS) or Trisomy 21 is the most common chromosomal disease and is characterized by possible heart defects, cognitive impairment and visual disorders. CASE PRESENTATION: We describe for the first time a 17-year-old Caucasian girl suffering from Down syndrome associated with vernal keratoconjunctivitis (VKC), a rare disorder of the anterior segment of the eye, characterized by intense photophobia, redness, watering eyes and itching due to an inflammatory-allergic reaction of the cornea and conjunctiva. On slit-lamp examination, the girl showed conjunctival hyperemia, papillary hypertrophy, giant papillae and corneal leukoma in right eye as a result of a previous corneal ulcer. A successful topical immunosuppressant therapy with cyclosporin 1% was started. CONCLUSION: So far, to our knowledge, this is the first description of VKC in a patient with DS. Finding an inflammatory-allergic disease such as VKC in DS is unusual but it must be taken into account because keratoconus, one of the most frequent eye pathologies in DS, can be secondary to an unrecognized VKC.

Unexplained regression in Down syndrome: Management of 51 patients in an international patient database.

Research to guide clinicians in the management of the devastating regression which can affect adolescents and young adults with Down syndrome is limited. A multi-site, international, longitudinal cohort of individuals with a clinical diagnosis of Unexplained Regression in Down syndrome (URDS) was collated through seven Down syndrome clinics. Tiered medical evaluation, a 28-item core symptom list, and interim management are described naturalistically. Improvement-defined by the percentage of baseline function on a Parent-reported Functional Score, overall improvement in symptoms on a Clinician-administered Functional Assessment, or report of management type being associated with improvement-was analyzed. Improvement rates using ECT, IVIG, and others were compared. Across seven clinics, 51 patients with URDS had regression at age 17.6 years, on average, and showed an average 14.1 out of 28 symptoms. Longitudinal improvement in function was achieved in many patients and the medical management, types of treatment, and their impact on function are described. Management with intravenous immunoglobulin (IVIG) was significantly associated with higher rate of improvement in symptoms at the next visit (p = 0.001). Our longitudinal data demonstrates that URDS is treatable, with various forms of clinical management and has a variable course. The data suggests that IVIG may be an effective treatment in some individuals. Our description of the management approaches used in this cohort lays the groundwork for future research, such as development of standardized objective outcome measure and creation of a clinical practice guideline for URDS.

Aberrant crosstalk between insulin signaling and mTOR in young Down syndrome individuals revealed by neuronal-derived extracellular vesicles.

INTRODUCTION: Intellectual disability, accelerated aging, and early-onset Alzheimer-like neurodegeneration are key brain pathological features of Down syndrome (DS). Although growing research aims at the identification of molecular pathways underlying the aging trajectory of DS population, data on infants and adolescents with DS are missing. METHODS: Neuronal-derived extracellular vesicles (nEVs) were isolated form healthy donors (HDs, n = 17) and DS children (n = 18) from 2 to 17 years of age and nEV content was interrogated for markers of insulin/mTOR pathways. RESULTS: nEVs isolated from DS children were characterized by a significant increase in pIRS1Ser636 , a marker of insulin resistance, and the hyperactivation of the Akt/mTOR/p70S6K axis downstream from IRS1, likely driven by the higher inhibition of Phosphatase and tensin homolog (PTEN). High levels of pGSK3ßSer9 were also found. CONCLUSIONS: The alteration of the insulin-signaling/mTOR pathways represents an early event in DS brain and likely contributes to the cerebral dysfunction and intellectual disability observed in this unique population.

Detection of iron deficiency in children with Down syndrome.

PURPOSE: Current American Academy of Pediatrics guidelines for children with Down syndrome (DS) recommend a complete blood count (CBC) at birth and hemoglobin annually to screen for iron deficiency (ID) and ID anemia (IDA) in low-risk children. We aimed to determine if macrocytosis masks the diagnosis of ID/IDA and to evaluate the utility of biochemical and red blood cell indices for detecting ID/IDA in DS. METHODS: We reviewed data from 856 individuals from five DS specialty clinics. Data included hemoglobin, mean corpuscular volume, red cell distribution width (RDW), percent transferrin saturation (TS), ferritin, and c-reactive protein. Receiver operating characteristic curves were calculated. RESULTS: Macrocytosis was found in 32% of the sample. If hemoglobin alone was used for screening, all individuals with IDA would have been identified, but ID would have been missed in all subjects. RDW had the highest discriminability of any single test for ID/IDA. The combination of RDW with ferritin or TS led to 100% sensitivity, and RDW combined with ferritin showed the highest discriminability for ID/IDA. CONCLUSION: We provide evidence to support that a CBC and ferritin be obtained routinely for children over 1 year old with DS rather than hemoglobin alone for detection of ID.

Unexplained regression in Down syndrome: 35 cases from an international Down syndrome database.

PURPOSE: An entity of regression in Down syndrome (DS) exists that affects adolescents and young adults and differs from autism spectrum disorder and Alzheimer disease. METHODS: Since 2017, an international consortium of DS clinics assembled a database of patients with unexplained regression and age- and sex-matched controls. Standardized data on clinical symptoms and tiered medical evaluations were collected. Elements of the proposed definition of unexplained regression in DS were analyzed by paired comparisons between regression cases and matched controls. RESULTS: We identified 35 patients with DS and unexplained regression, with a mean age at regression of 17.5 years. Diagnostic features differed substantially between regression cases and matched controls (p < 0.001 for all but externalizing behaviors). Patients with regression had four times as many mental health concerns (p < 0.001), six times as many stressors (p < 0.001), and seven times as many depressive symptoms (p < 0.001). Tiered medical evaluation most often identified abnormalities in vitamin D 25-OH levels, polysomnograms, thyroid peroxidase antibodies, and celiac screens. Analysis of the subset of patients with nondiagnostic medical evaluations reinforced the proposed definition. CONCLUSIONS: Our case-control evidence supports a proposed definition of unexplained regression in Down syndrome. Establishing this clinical definition supports future research and investigation of an underlying mechanism.

Differences in morbidity and mortality in Down syndrome are related to the type of congenital heart defect.

Morbidity and mortality in Down syndrome (DS) are mainly related to congenital heart defects (CHDs). While CHDs with high prevalence in DS (typical CHDs), such as endocardial cushion defects, have been extensively described, little is known about the impact of less common CHDs (atypical CHDs), such as aortic coarctation and univentricular hearts. In our single-center study, we analyzed, in observational, retrospective manner, data regarding cardiac features, surgical management, and outcomes of a cohort of DS patients. Literature review was performed to investigate previously reported studies on atypical CHDs in DS. Patients with CHDs were subclassified as having typical or atypical CHDs. Statistical analysis was performed for comparison between the groups. The study population encompassed 859 DS patients, 72.2% with CHDs, of which 4.7% were atypical. Statistical analysis showed a significant excess in multiple surgeries, all-cause mortality and cardiac mortality in patients with atypical CHDs (p = .0067, p = .0038, p = .0001, respectively). According to the Kaplan-Meier method, survival at 10 and 40 years was significantly higher in typical CHDs (99 and 98% vs. 91 and 84%, log rank <0.05). Among atypical CHDs, it seems that particularly multiple complex defects in univentricular physiology associate with a worse outcome. This may be due to the surgical difficulty in managing univentricular hearts with multiple defects concurring to the clinical picture or to the severity of associated defects themselves. Further studies need to address this specific issue, also considering the higher pulmonary pressures, infective complications, and potential comorbidities in DS patients.

PNPLA3 gene polymorphism is associated with liver steatosis in children with Down syndrome.

BACKGROUND AND AIMS: We previously demonstrated that children with Down syndrome (DS) exhibited a greater risk of steatosis than the general pediatric population. This trend was independent of obese phenotype, thus suggesting a role of genetic predisposition. Therefore, we investigated the prevalence of non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS) in function of genetic susceptibility and adipocytokine levels in children with DS. METHODS AND RESULTS: A total of 84 Caucasian children with DS (age range 5-17 years), were included in this study. For all children, we collected data on anthropometric and biochemical parameters, and liver ultrasound (US). We also measured adipocytokines circulating levels and specific polymorphisms closed to NAFLD. We found a prevalence of 64.3% of liver steatosis at US, with a severe steatosis of about 4% in children with DS. The presence of steatosis in children with DS was associated with the presence of patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 variant, which also correlated with interleukin (IL)-6 levels. Moreover, we found that the 52.4% had a waist circumference > 90th percentile, 21.4% were hypertensive, 7.14% had hyperglycemia, 9.5% had hypertriglyceridemia, and 17.9% showed high-density lipoprotein cholesterol ≤ 40 mg/dl. Finally, the IL-6 and adiponectin levels correlated with steatosis, and several adipocytokines correlated with single MetS traits in children with DS. CONCLUSION: The present study explores for the first time potential pathomechanisms connecting pediatric NAFLD and MetS in DS. We found that the PNPLA3 variant is associated with steatosis, but not with MetS, in children with DS.

Bartonella henselae in Italy: a rare seasonal infection.

BACKGROUND: Symptomatic Bartonella henselae infection is considered rare in Europe. Cat fleas transmit the microorganism between cats, but their role in transmission of B. henselae to humans has not been defined. The aim of our study was to perform a retrospective study of detected cases at our Hospital. METHODS: We retrospectively analyzed data of all children showing lymphadenopathy and a 4-fold increase in specific IgM for B. henselae over the period from June 2010 to May 2015. We therefore examined clinical data, laboratory exams in order to achieve a description of the expression of Bartonella infection in our series: age, geographical area of origin, symptoms, laboratory exams, the seat of the swelling lymph nodes with ultrasound description, and data on biopsy of lymph node when performed. RESULTS: We could identify a total of 7 patients (4 females, range of age: mean age 8.75±2.87 SD): three cases in 2011 and 1 case per year in 2010, 2012, 2013 and 2014 with an average distance between one case and the sequent of 246.16±214.54 days. All patients came from small towns with no preference between the inland and coastal areas. The infection was characterized only by lymphadenopathy with nonspecific alterations at blood tests and with no history of cat scratch. CONCLUSIONS: By our experience, Bartonella infection presents as a seasonal disease with increased incidence in autumn, with peaks in October, and a decrease after spring. In conclusion, infection with B. henselae is an issue to keep in consideration in all cases of lymphadenopathy, especially in children coming from small towns even without a declared cat scratch.

B-cell activation with CD40L or CpG measures the function of B-cell subsets and identifies specific defects in immunodeficient patients.

Around 65% of primary immunodeficiencies are antibody deficiencies. Functional tests are useful tools to study B-cell functions in vitro. However, no accepted guidelines for performing and evaluating functional tests have been issued yet. Here, we report our experience on the study of B-cell functions in infancy and throughout childhood. We show that T-independent stimulation with CpG measures proliferation and differentiation potential of memory B cells. Switched memory B cells respond better than IgM memory B cells. On the other hand, CD40L, a T-dependent stimulus, does not induce plasma cell differentiation, but causes proliferation of naïve and memory B cells. During childhood, the production of plasmablasts in response to CpG increases with age mirroring the development of memory B cells. The response to CD40L does not change with age. In patients with selective IgA deficiency (SIgAD), we observed that switched memory B cells are reduced due to the absence of IgA memory B cells. In agreement, IgA plasma cells are not generated in response to CpG. Unexpectedly, B cells from SIgAD patients show a reduced proliferative response to CD40L. Our results demonstrate that functional tests are an important tool to assess the functions of the humoral immune system.

Nonalcoholic Fatty Liver Disease in Italian Children with Down Syndrome: Prevalence and Correlation with Obesity-Related Features.

OBJECTIVE: To assess the prevalence of overweight/obesity in a cohort of Italian children with Down syndrome (DS) and to investigate the correlation of both obesity and DS with nonalcoholic fatty liver disease (NAFLD). STUDY DESIGN: We enrolled 280 children with DS (age range 5-18 years), who were referred to the DS outpatient clinic of the Bambino Gesù Children's Hospital in Rome. For all children, we collected the clinical history and measured anthropometric variables. Eighty-four of 280 children with DS were selected to undergo liver ultrasound scanning to evaluate the presence of NAFLD. RESULTS: Italian children with DS exhibited a prevalence of 19.64% for overweight and 12.14% for obesity. The prevalence of NAFLD in nonobese (45%) and overweight/obese (82%) children with DS is greater than in the European pediatric nonobese (5.7%) or obese population (33%). Moreover, the severity of liver brightness on ultrasound scan correlated positively with body mass index, triglycerides, low-density lipoprotein-cholesterol, and leptin levels and negatively with adiponectin. CONCLUSIONS: We demonstrated that, independently from the obese phenotype, children with DS display a greater risk to develop NAFLD than the general pediatric population.

Hospital-acquired rotavirus and norovirus acute gastroenteritis in a pediatric unit, in 2014-2015.

The occurrence of hospital-acquired acute gastroenteritis (AGE) is a major concern for public health. RotavirusA (RVA) and norovirus (NoV) are common causes of viral AGE in the pediatric population, and their role in nosocomial infections has been proven, remaining poorly investigated. To investigate RVA and NoV in hospital-acquired AGE, 55 stool samples from children with nosocomial AGE were collected between May 2014 and May 2015. To evaluate virus spreading routes, 51 environmental swabs were collected from staff and patients' rooms. Stools were tested for both RVA and NoV RNA by reverse-transcription-PCR. Nucleotide sequencing and phylogenetic analysis were performed to characterize the viruses. Forty-seven of 55 cases analyzed resulted positive for RVA. The predominant genotype was G4P[8] (18/55) followed by G1P[8] (14/55). Mixed RVA infections were also detected (7/55). Twenty-two samples were positive for NoV, and GII.4 was revealed to be the predominant genotype. Seventeen samples were positive for both RVA and NoV. This study aimed to evaluate the burden of norovirus and rotavirus nosocomial AGE, contributing to identify the environment source of infections and to activate effective strategies for intervention. The reduction in nosocomial AGE cases is an important aspect, considered the worsened disease course in transplant, cancer, and intensive care unit inpatients.

Reduced numbers of switched memory B cells with high terminal differentiation potential in Down syndrome.

Children with Down syndrome (DS) have increased susceptibility to infections and a high frequency of leukemia and autoimmune disorders, suggesting that immunodeficiency and immune dysfunction are integral parts of the syndrome. A reduction in B-cell numbers has been reported, associated with moderate immunodeficiency and normal immunoglobulin levels. Here, we compared B-cell populations of 19 children with DS with those in healthy age-matched controls. We found that all steps of peripheral B-cell development are altered in DS, with a more severe defect during the later stages of B-cell development. Transitional and mature-naïve B-cell numbers are reduced by 50% whereas switched memory B cells represent 10-15% of the numbers in age-matched controls. Serum IgM levels were slightly reduced, but all other immunoglobulin isotypes were in the normal range. The frequency of switched memory B cells specific for vaccine antigens was significantly lower in affected children than in their equivalently vaccinated siblings. In vitro switched memory B cells of patients with DS have an increased ability to differentiate into antibody-forming cells in response to TLR9 signals. Tailored vaccination schedules increasing the number of switched memory B cells may improve protection and reduce the risk of death from infection in DS.

Sleep and behavioral problems in Down syndrome: differences between school age and adolescence.

Background: Individuals with Down syndrome (DS) are at risk of developing sleep problems. In spite of the well-established knowledge on the presence of sleep difficulties in DS individuals and the associated emotional and behavioral problems, less is known about the possible differences in the kind of associations between sleep and emotional/behavioral problems across different age ranges. Methods: In this retrospective study, we included 289 participants with DS aged 6-18 years with the aims to explore differences in the distribution of sleep problems between specific age groups (school age vs. adolescence) and to identify specific age-based associations between sleep problems and emotional/behavioral problems. Results: Some differences in the distribution of sleep problems have emerged between age groups. Moreover, differences in the patterns of association between emotional/behavioral difficulties and sleep problems-in particular, sleep-related breathing difficulties and parasomnias-have been observed. However, sleep-wake transition disorders and excessive daily somnolence appear to be related to emotional and behavioral problems (both internalizing and externalizing), in general, across school age and adolescence. Discussion: These results remark the importance of appropriate neuropsychiatric and psychological evaluation taking into account the age-specific needs and features of individuals with DS.

Emotional and behavioral features associated with subclinical hypothyroidism in children and adolescents with Down syndrome.

Background: Subclinical hypothyroidism (SH) is particularly frequent in individuals with Down syndrome (DS). Despite the amount of evidence suggesting SH is associated with psychopathological symptoms and sleep problems in general population, poor is known about the emotional and behavioral features associated with SH in children with DS. Objective: The first aim of the current study was to investigate differences in emotional and behavioral profiles between a group of children with DS exhibiting co-occurring SH and a group of age and BMI-matched children with DS without co-occurring SH. The second aim of the present study was to investigate differences in sleep disturbances between these groups. Methods: We included in this retrospective study 98 participants with DS aged 3-18 years with the aim to explore differences in emotional/behavioral problems as well as in sleep difficulties between children with DS with or without co-occurring SH. Results: Participants with co-occurring SH exhibited significantly higher scores at several scales of the Conners' Parent Rating Scales Long Version - Revised. However, they did not exhibit more sleep problems than control group. Conclusion: These results provide specific indications for psychological and neuropsychiatric evaluation of children with DS with suspected or diagnosed SH, highlighting the importance of a multidisciplinary approach in clinical care for children and adolescents with DS.

Down Syndrome in FPIES: An Overwhelming and Unexpected Prevalence.

Down syndrome (DS) is one of the most common chromosomal anomalies. Gastrointestinal disorders in DS are predominantly related to anatomical anomalies and celiac disease. In 2015, the first two cases of non-IgE-mediated food allergy in patients with DS were described. However, gastrointestinal symptoms experienced by subjects with DS have never been related to a possible non-IgE-mediated food allergy and a Food Protein-induced Enterocolitis syndrome (FPIES). A retrospective descriptive single-center study was conducted. Subjects included were children with acute FPIES who entered our institutional follow-up protocol between January 2013 and January 2020. Among the 85 patients (forty-nine boys-57.6%), ten (11.76%) were children with DS. In our population, the FPIES triggers included different foods (such as milk, egg, fruit, fish, wheat, soy, beef, etc.). Nine patients with DS showed FPIES reactions after ingesting cow's milk (one even with beef and three with soy), while the last one was affected by FPIES to fish. Considering the subgroup of patients affected by cow's milk FPIES (40 subjects overall), 22.5% had a diagnosis of DS. Patients with DS experienced acute FPIES reactions with a severity degree slightly higher than that reported in other patients, ranging from mild-moderate to severe or very severe. During the acute reactions, the patients with DS showed increased white blood cell production, absolute neutrophil count and C-reactive protein levels. This series provides a starting point for novel hypothesis-testing clinical research and possible specific immunological alterations in FPIES children with or without DS.

Assessment of oppositional defiant disorder and oppositional behavior in children and adolescents with Down syndrome.

Introduction: Children and adolescents with intellectual disability (ID) exhibit higher rates of oppositional defiant disorder (ODD) than typically developing (TD) peers. However, studies focusing on the investigation of ODD prevalence in youth with Down syndrome (DS) are still limited. Methods: The current study aimed to investigate the prevalence of ODD clinical and subclinical symptoms in a group of 101 youth with DS (63 boys, 38 girls) ranging in age from 6 to 18 years. Moreover, the prevalence of ODD symptoms, as detected by means of three parent-report questionnaires, was compared with that detected by a semi-structured psychopathological interview, namely, the Schedule for Affective Disorders and Schizophrenia for School Aged Children Present and Lifetime (K-SADS) Version Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5). Results: We found that 17% of participants met diagnostic criteria for ODD on the K-SADS, whereas 24% exhibited subclinical symptoms. Results also suggest good specificity of Swanson, Nolan, and Pelham-IV Rating Scale (SNAP-IV), Conners' Parent Rating Scales Long Version (CPRS) and Child Behavior Checklist (CBCL) in detecting ODD symptoms. The investigation of the agreement in the prevalence rates of clinical and subclinical symptoms of ODD between K-SADS and the parent-report questionnaires indicated CPRS as the parent-report questionnaire with the best agreement with K-SADS. Discussion: This study provides support for the use of parent-report questionnaires to assess ODD symptoms in children and adolescents with DS by evaluating their levels of agreement with a semi-structured psychopathological interview. In particular, our results suggest that CPRS could be considered a suitable screening tool for ODD clinical and subclinical symptoms in youth with DS.